Structural Abnormalities of the Craniofacial Complex and Congenital Malformations

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Pediatric Oral Health

Structural Abnormalities of the Craniofacial Complex and Congenital Malformations

Andrew E. Poole, BDS, MS, PhD,* and Deborah A. Redford-Badwal, DDSt

Three percent to 7% of all babies born have at least one congenital abnormality. Most likely, because of the complexity and potential vulnerability of the region, 75% of these defects affect the craniofacial complex (cranial vault, face, neck, and oral cavity). 19 Specific recognizable alterations of craniofacial form, structure, and function are often associated with various congenital disorders and syndromes. Many of these conditions have been classified by their craniofacial abnormalities because their prominence often makes them cardinal features. Thus, it is important for the clinician to be sensitive to changes in the craniofacial structures that can alert the practitioner to the presence of other disease or structurally abnormal entities. In order to describe dysmorphic changes in the craniofacial structures, it is important to recognize normal changes and be able to accurately describe abnormal changes using the currently available nomenclature and classification. In this article we provide a brief review and discussion of the general principles of craniofacial dysmorphology and the methods used to recognize, describe, and classify craniofacial dysmorphology. We then describe specific abnormalities seen in the dentition and other craniofacial structures and the syndromes or disorders with which they might be associated. This article is not intended to be an exhaustive list of all the syndromes associated with any given feature, but rather give examples of some of the important concepts.

* Director, Craniofacial Disorders Team, and Professor of Pediatric

Dentistry, University of Connecticut Health Center, Farmington, Connecticut t Fellow, Division of Genetics, Department of Pediatrics and Pediatric Dentistry, and Biostructure and Function, University of Connecticut Health Center, Farmington, Connecticut

Pediatric Clinics of North America-Vol. 38, No.5, October 1991

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GENERAL PRINCIPLES OF DYSMORPHOLOGY The finding of three or more dysmorphic features in the same individual often can be considered a syndrome. When multiple developmental defects are seen in an infant, the clinician should be alerted to consider a syndrome and consult a genetics team. Geneticists are those health care providers who are most familiar with many of these conditions and can most easily recognize specific syndromes. Syndromes can be caused by chromosomal abnormality, single gene defects, or environmental agents or insults. With the aid of chromosome analysis, family pedigree, or careful attention to prenatal history, the labeling of a disorder may be possible. This is done with the aid of various resources, including computer search programs. The real value of syndrome identification lies in the ability to predict natural history, anticipated structural or functional expression, and the estimated recurrence risk for that individual and other family members. Equally, with careful delineation of characteristics, clues to the cause of the disorder may be obtained. If a syndrome characteristic of the findings cannot be found, the disorder is either a provisionally unique syndrome to that family or a chance association of these abnormalities for reasons unknown. Provisionally unique syndromes are sometimes published to ascertain if other individuals with similar findings have been seen in other clinics. Syndromes have been named after individuals, after the affected systems or organs, after the major symptoms, and by letters of the alphabet. International collaboration, however, has been initiated to standardize syndrome nomenclature and to organize syndromes by the developmental events by which they arise. 18 A summary of these different groups of syndromes is given in Table 1. This classification is not all-inclusive, nor does it always accurately describe the cause. Many malformations occur alone or as part of a larger malformation (e.g., cleft palate). This may result from a single gene defect, a combination of genes and environment, or from a pure environmental insult. Cohen4 adds to this list two other categories of syndromes: dysmetabolic syndromes and dysplastic syndromes. Dysmetabolic syndromes are the result of a metabolic defect, whereas dysplastic syndromes result from abnormalities at the tissue level in cell division. All of these types of abnormalities find expression in the craniofacial complex as well as the rest of the body. In general, it is ultimately desirable to trace these defects to the molecular level, but at present it is often convenient to think of them as primarily cell defects (dysmetabolic), tissue defects (dysplastic), organ defects (malformations), or regional defects (deformations).2o Abnormalities of the dentition can speculatively include dysmetabolic defects (dentinogenesis imperfecta), dysplastic defects (hypoplastic amelogenesis imperfecta), malformation defects (supernumerary or single missing teeth), and deformation defects (multiple missing teeth). The latter is thought to be caused by failure in tooth induction before morphogenesis.

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Table 1. Theoretical Examples of the Type of Anomaly Seen with the Different Etiologic Types of Defect TYPE

DEFECT

Malformation

Deformation

Disruption

Malformation sequence

Malformation syndrome

A primary structural defect resulting from a localized error in programmed morphogenesis An alteration in the shape or structure of a previously normal part resulting from external forces A defect that results from extrinsic breakdown of originally normal developmental processes A defect resulting from interruption of a specific step in development, which leads to subsequent abnormalities Recognized patterns of malformation with a common cause but not the result of a single localized error in morphogenesis

EXAMPLES

Cleft lip, cleft palate, polydactyly, holoprosencephaly Plagiocephaly, club foot, micrognathia Amniotic bands

Robin sequence, (U-shaped cleft palate, micrognathia, glossoptosis) Down syndrome

Clearly, abnormalities of the dentition can be associated with generalized defects in calcification (e.g., pseudohypoparathyroidism), in skin and its appendages (e.g., ectodermal dysplasia), in growth disorders affecting bone matrix synthesis (e.g., hypopituitarism), and in generalized protein-mucopolysaccharide synthesis (e.g., phenylketonuria and the mucopolysaccharidoses). These syndromes are of the dysmetabolic type. A large category of dental and orofacial defects fall into a nonspecific category of abnormalities that, without knowledge of the nature of the defect, could be part of many syndromes-for example, enamel hypoplasias or discolored teeth.20 Under the assumption, however, that "the more abnormalities that can be recognized in a given syndrome, the easier the condition is to diagnose,"4 the recording of those minor and major anomalies is an important step in delineating a diagnosis and managing the needs of the patient (Table 2).

IDENTIFICATION AND RECOGNITION OF CRANIOFACIAL DYSMORPHOLOGY Syndrome identification initially necessitates a routine diagnostic approach, including an accurate history and physical examination. As with any developmental defect, a precise prenatal history and newborn photographs are useful. Postnatal growth and development monitoring are also valuable, particularly for cases in which the syndrome is

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Table 2. Recognizable Abnormalities of the Orofacial Structures HEAD (MACROCEPHALY, MICROCEPHALY)

Aberrant hair pattern Malformed cranial vault High forehead Wide fontanelles Mectopic suture Prominent supraorbital ridges Flattened occiput EXTERNAL EARS

Auricular tags Auricular pits Abnormal helix Protuberant ears Low-set ears Narrow external auditory meatus Rotated ears Small ears EXTERNAL EYES

Absence of eyelashes (extra eye lashes) Epicanthal folds Upward-slanting palpebral fissures Downward-slanting palpebral fissures Hypotelorism Hypertelorism Telecanthus Size and shape of palpebral fissures Confluent eyebrows Depressed nasal bridge Coloboma

MAXILLA-MANDIBLE

Flattened malar region Large upper jaw Micrognathia Prognathic jaw Microstomia Macrostomia Downturned mouth ORAL CAVITY

Cleft lip Prominent lips Long philtrum Lip pits High arched palate (submucous cleft) Cleft palate Abnormal frenula Macroglossia Microglossia Bifid tongue Abnormal speech (hypernasality) Hypertrophied ridges FACIES

Flattened Coarse Expressionless Broad Narrow and tall Triangular Asymmetric

NOSE

Flat nasal bridge Anteverted nostrils Narrow nose Large, broad nose

not clear at birth and the child literally grows into a diagnosis. A good family history, with a detailed pedigree, and photographs of other family members at various ages prove invaluable, particularly where family resemblances have been described. Physical examination should cover all systems, with a special emphasis on both major and minor defects throughout the body. The presence of three or more minor anomalies in the newborn strongly predisposes the infant to have a major anomaly involving one or more systems. 19 The characteristics described in Table 2 represent some of the cardinal features of craniofacial dysmorphology. The examination of the face and oral cavity can consist of both qualitative (visual) and quantitative (measurement) observations. Both are reliable methods that skilled observers use to determine craniofacial dysmorphology, but rarely can only one method be used. 20 Quantitation of facial form or measurement of organ size (e.g., the tongue) is often difficult to perform using current methodology, and

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therefore subjective clinical assessment is essential. Major departure from normal size, function, or shape are very obvious, but mild to moderate differences may not be recognizable yet still be important to use in diagnosing a syndrome. These less obvious differences may be recognized better as the child grows or as other cardinal features of the syndrome are delineated. Another confounding factor in syndrome identification is the differences in expressivity of the features of the condition. This can occur whether the syndrome is inherited or sporadic, but can confuse the inheritance when a parent or relative expresses only subtle manifestations of the condition. Only after careful examination of all family members does the transmission from parent to child become more clear. Photographs of distant relatives who are not available for examination may also be essential to ensure accuracy of the pedigree analysis. Variation in penetrance (transmission from generation to generation) and expressivity (appearance within an individual) are often a characteristic of dominant inheritance. Obviously to the practiced eye, the gestalt of a syndrome can be extremel(;; important, particularly where accurate quantitation is not possible. 2 Nevertheless, as better normal standards continue to be collected, many abnormal craniofacial features can be quantified and the features of a particular syndrome more precisely delineated. Direct Measurement of the Face The single most useful predictor of brain development is head circumference. With standard charts available from the Natiorial Center for Health Statistics, measurement of head circumference is done in most pediatric offices and is particularly useful in children and adults with dysmorphic features. Microcephaly and, to some degree macrocephaly, are indicators of a poor prognosis for normal brain growth and, hence, mental development, in the newborn. These are often found as part of many syndromes affecting the head and face region. Accompanying the measurement of head circumference should be the examination of the cranial vault for size of the fontanelles, sutural anatomy (particularly ridging), and the overall shape and symmetry of the cranial bones. The amount, distribution, texture, and pattern of the hair are of importance and should be evaluated at the same time. Measurement of the face can be performed using the procedures of Feingold and Bossert. 9 The distance between the eyes (inner and outer canthal distance) and the interpupillary distance (hypotelorism and hypertelorism) are important observations to be recorded in the examination of the face, and comparisons should be made to the normal values found in standard graphs. 9 Similar measurements exist for position and size of the ears, breadth of the nose, nasolabial length, oral opening (intercommissural distance), and lip thickness. In addition, upper, midface, and lower facial heights, as well as skull height, can all be made directly on the face with appropriate calipers and rulers. Because many of these values have specific landmarks from which measurements are made, qualitative assessment of facial symmetry is essential to the interpretation of these data.

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Indirect Measurement of the Face Tomographic radiographs, plane radiographs, and study casts of the jaws and teeth are often useful in the interpretation of craniofacial dysmorphology and oral abnormalities. Cephalometric films of the skull allow measurements of both the bony and soft tissues of the face to be compared with standard measurements of normal individuals (Fig. 1). These radiographs, both lateral and posteroanterior, are taken in a standard head-holder that allows for accurate reproduction of the head from one subject to the next and for rotations of the head in three dimensions to be minimized. These films are particularly useful in determining whether, for example, flattening of the malar region is the result of bony or soft-tissue abnormalities. Measurement of the length of the mandible using well-established landmarks may also quantitatively determine if micrognathia exists and may subsequently aid in the prediction of "catch-up." These radiographs should be interpreted with care, however, because in children with dysmorphology, cephalometric radiographs may not be as easy to take in a standardized fashion because of displacement of landmark structures and, therefore, key measurement points not as readily defined. Computed tomography (CT) and magnetic resonance (MR) imaging are also beginning to playa major diagnostic role in craniofacial syndrome identification. Of special value are the computerized threedimensional reconstructed CT scans that enable accurate visualization of suture anatomy needed in evaluating craniosynostosis (Fig. 2). Synostosis of sphenoid sutures is often missed when plane radiographic films are used for evaluation instead of the three-dimensional CT scan. Visualization of premature closure of these sutures can be a key element in diagnosing Apert and Crouzon syndromes, for example. These scans are also an essential part of planning reconstructive surgical treatment for these disorders. Quantification of craniofacial structures using MR imaging or CT scans is only just beginning; future diagnostic accuracy will most likely rely heavily on these techniques. Dental radiographs are essential for determining tooth development (calcification), missing and supernumerary teeth, and crown-root tooth dimension. Radiographs are also of value in recording the general structure and thickness of enamel and dentin as well as the size and shape of the pulp cavity. Study models of the teeth and jaws are especially useful in measuring jaw size, palatal vault dimensions, tooth anatomy, and occlusion. Interpretation of these dental findings may require the assistance of a dentist in completely listing all the features of a syndrome.

DENTAL ABNORMALITIES ASSOCIATED WITH GENERALIZED CONGENITAL DISORDERS The development of the dentition is but a single factor in the highly complex phenomenon of craniofacial development. Because of the unique pattern of growth and development and the remarkable

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B Figure 1. Cephalometric analysis of craniofacial structures. A, Cephalometric radiograph of patient with the Marfan syndrome. Note the ear rods in position. A nasal rest and cheek pointer are also used to ensure reproducible radiographic alignment. B, Tracing of this radiograph from which measurements can be made.

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Figure 2. Three-dimensional reconstruction of CT scan of a week-old infant with craniosynostosis. Arrow indicates premature fusion of the right coronal suture.

metabolic stability of their structure, the teeth provide the clinician with an opportunity to examine alterations in form and structure and to extrapolate these observations to periods of metabolic disru~tion that occurred during the developmental history of that tooth. 2 The sequence and regularity of this development subject the dentition to a wide range of potential disturbances extending over a significantly long period of time. The primary teeth contain a permanent record of metabolic or environmental disturbances that occur during a specific period of tooth development and during incremental growth that begins during the second trimester of pregnancy. Similarly, the permanent dentition provides an accurate record of disturbances in normal developmental processes for a period that extends from the time of birth to approximately the twelfth year of postnatallife. 20 The next two tables show the chronologic development of both the primary (Table 3) and permanent dentition (Table 4). Familiarity with this sequence of dental development can be of value in determining the nature and timing of a disturbance. This can be of particular importance in the evaluation of a patient with congenital anomalies. The phenomena of dental development have been divided into several stages based on histologic findings: (1) initiation or bud stage;

Table 3. Normal Chronologie Development of Primary Teeth

TOOTH

INITIATION (WEEK IN UTERO)

Central incisor Lateral incisor Canine First molar Second molar

7 7 7.5 8 10

CALCIFICATION BEGINS (WEEK IN UTERO)

14 (13-16) 16 (14.5-16.5) 17 (15-18) 15.5 (14.5-17) 18.5 (16-23.5)

CROWN COMPLETED (MONTH)

ERUPTION (MONTH)

ROOT COMPLETED (YEAR)

ROOT RESORPTION BEGINS (YEAR)

TOOTH SHED (YEAR)

1-3 2-3 9 6 10-12

6-9 7-10 16-20 12-16 20-30

1.5-2 1.5-2 2.5-3.25 2-2.5 3

5-6 5-6 6-7 4-5 4-5

7-8 7-9 10-12 9-11 11-12

From Gorlin RJ, Pindborg JJ, Cohen MM Jr: Syndromes of the Head and Neck, ed 2. New York, McGraw-Hill, 1976. Data sources: Logan WHG, Kronfeld R: Development of the human jaws and surrounding structures from birth to the age of 15 years. J Am Dent Assoc 20:379, 1933; Schour I, MassIer M: Studies in tooth development. The growth pattern of human teeth. J Am Dent Assoc 27:1918, 1940; Lunt RC, Law DB: A review of the chronology of calcification of the deciduous teeth. J Am Dent Assoc 89:599, 1974; with permission .

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Table 4. Normal Chronologie Development of Secondary Teeth (YEAR)

ERUPTION (YEAR)

ROOT COMPLETED

CALCIFICATION BEGINS

5-5.25 in utero 5-5.25 in utero 5.5-6 in utero Birth 7.5-8 3.5-4 in utero 8.5-9 3.5-4 (yr)

3-4 months 1 year 4-5 months 1.5-1. 75 years 2-2.5 years Birth 2.5-3 years 7-9 years

4-5 4-5 6-7 5-6 6-7 2.5-3 7-8 12-16

7-8 8-9 11-12 10-11 10-12 6-7 12-13 17-25

10 11 13-15 12-13 12-14 9-10 14-16 18-25

5-5.25 in utero 5-5.25 in utero 5.5-6 in utero Birth 7.5-8 3.5-4 in utero 8.5-9 3.5-4 (yr)

3-4 months 3-4 months 4-5 months 1. 75-2 years 2.25-2.5 years Birth 2.5-3 years 8-10 years

4-5 4-5 6-7 5-6 6-7 2.5-3 7-8 12-16

6-7 7-8 9-11 10-12 11-12 6-7 11-13 17-25

9 10 12-14 12-13 13-14 9-10 14-15 18-25

CROWN COMPLETED

INITIATION TOOTH

Maxilla Central incisor Lateral incisor Canine First premolar Second premolar First molar Second molar Third molar Mandible Central incisor Lateral incisor Canine First premolar Second premolar First molar Second molar Third molar

(MONTH)

(YEAR)

From Gorlin RJ, Pindborg JJ, Cohen MM Jr: Syndromes of the Head and Neck, ed 2. New York, McGraw-Hill, 1976. Data sources: Logan WHG, Kronfeld R: Development of the human jaws and surrounding structures from birth to the age of 15 years. J Am Dent Assoc 20:379, 1933; Schour I, MassIer M: Studies in tooth development. The growth pattern of human teeth. J Am Dent Assoc 27:1918,1940; with permission.

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(2) proliferation or cap stage; (3) histodifferentiation or bell stage; (4) morphodifferentiation; (5) apposition; (6) calcification; and (7) eruption20 (Fig. 3, Table 5). Divisions between these stages are not absolute because the different tissues undergo transitions between stages at different rates and in different locations. Apposition and calcification occur simultaneously in the same tissue. Abnormalities resulting from genetic insults, environmental insults, or a combination of both are known to occur at each of the developmental stages and affect the tissues undergoing development at that stage. Abnormalities in Initiation and Proliferation Problems occurring during initiation and proliferation are believed to produce anomalies in the number of teeth. This can produce congenitally missing teeth in either the primary or permanent dentitions. Terms that are used in association with congenitally absent teeth include hypodontia, oligodontia, and anodontia. Hypodontia refers to the situation in which a single tooth or a few teeth are missing. Oligodontia is the absence of multiple teeth (Fig. 4) and anodontia

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ERUPT/ON . ATnh'ON Figure 3. Human primary incisor, from bud stage through eruption. Enamel and bone are seen in black. (Adapted from Stewart RE, Poole AE: The orofacial structures and their association with congenital abnormalities. Pediatr Clin North Am 29:547, 1982.)

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Table 5. The Stages of Tooth Development and the Expected Dental Abnormalities Which Can Result from Their Disturbance STAGE OF DEVELOPMENT

Initiation and proliferation

Histodifferentiation

Morphodifferentiation

Apposition Calcification Eruption

DEFINITION

ABNORMALITIES

An inductive event of the early dental epithelium to the underlying mesenchymal component, resulting in development of the dental lamina and tooth bud Series of cellular changes result in the formation of three specialized cell types Tooth germ assumes the form of the developing crown (i.e., incisor, molar) Laying down of the matrix Mineralization of the organic phase Active movement of the tooth into the oral cavity

Congenitally missing teeth

Amelogenesis imperfecta, dentinogenesis imperfecta, cemental dysplasia Conical crowns, mulberry teeth, taurodontism Microdontia, macrodontia H ypocalcification, hypoplasia Impacted teeth, neonatal teeth

Figure 4. Oral cavity of a child with multiple missing teeth (note atrophic ridges) and peg-shaped central incisors.

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Table 6. Syndromes and Systemic Disorders Associated with Abnormalities of Tooth Number HYPODONTIA

Albright hereditary osteodystrophy Down syndrome Ectodermal dysplasia (several varieties) Goltz syndrome (focal dermal hypoplasia) HaBermann-Streiff syndrome Incontinentia pigmenti syndrome Orofacial digital syndrome Cleft lip and palate SUPERNUMERARY TEETH

Cleidocranial dysplasia Gardner syndrome Hallermann-Streiff syndrome Cleft lip and palate

involves the absence of all teeth. Oligodontia or anodontia are more commonly seen in the severe forms of ectodermal dysplasia (Table 6). Abnormalities of tooth number can also include hyperdontia or supernumerary teeth (Fig. 5). Although the exact cause is still unknown, it is believed that supernumerary teeth result from an overproliferation of cells at various locations along the developing dental lamina. 2o Hyperdontia as well as hypodontia affect certain teeth or regions of the dentition more frequently than other regions. The primary dentition is not affected by anomalies in initiation or proliferation as often as the permanent dentition. Multiple supernumerary teeth are

Figure 5. Oral cavity showing a supernumerary (extra) upper incisor.

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commonly associated with certain genetic conditions such as cleidocranial dysplasia, Gardner syndrome, and cleft lip and palate, but also have been associated with other syndromes 21 (Table 6). Abnormalities in Histodifferentiation and Morphodifferentiation Abnormalities in histodifferentiation and morphodifferentiation result in changes within the dental organ itself. Failure in histodifferentiation of any of the four different cell types can result in absent or very abnormal organic matrix. Likewise, failure in morphodifferentiation results in abnormal tooth shape. Abnormalities in Tooth Structure As mentioned earlier, the crowns of developing teeth, by the very nature of their developmental history, provide a permanent record of any metabolic or systemic disturbance that occurred during the course of the tooth's formation. 2o This is attributable to the fact that once the enamel and dentin are formed, they do not undergo remodeling, and therefore, insults that have occurred during their formation remain permanently recorded there. Systemic insults, such as a prolonged period of high fevers, nutritional deficiencies, congenital infections, and certain drugs, all can affect the enamel-forming cells, the ameloblasts, or the dentin-forming cells, the odontoblasts (Fig. 6). There are documented conditions in which the developmental problem lies specifically within the enamel or dentin. One such grour of conditions is amelogenesis imperfecta. Amelogenesis imperfecta is a relatively rare developmental disturbance of the dentition that occurs either as a result of an abnormal functioning of the ameloblasts or as an

Figure 6. Chronological defect of tooth development. Note that the defect has distinct lines of structural abnormality corresponding to a specific time in development.

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abnormality in calcification of the enamel matrix secreted by the ameloblasts. 21 This group of conditions is classified by the clinical appearance of the defect, the stage in enamel development in which the abnormality occurs, and the pattern of genetic transmission in families 24 (Fig. 7). When the affected tissue is the dentin, the odontoblasts are not functioning properly. These disorders can generally be divided into two categories of defects: the dentinogenesis imperfectas and the dentin dysplasias. 15 Dentinogenesis imperfecta can be seen in isolation or in combination with skeletal abnormalities such as osteogenesis imperfecta. It is usually inherited in an autosomal dominant fashion. Dentin defects, when seen in isolation, are less variable between the primary and permanent dentitions and within family members. The conditions in Figure 8 represent a problem with the formation of the dentin. 21 Abnormalities in cementum are less clear, but generally affect the attachment of the teeth to bone, i.e., the periodontal ligament. Absence of cementum can lead to tooth loss, as seen in hypophosphatasia, in which teeth are lost spontaneously without evidence of local disease. A condition in which excess cementum produces cementomas also exists, and this presents with difficulties in extractions and can cause ankylosis or permanent tooth-bone attachment. Familial forms of ankylosis have been described, but it is unclear if this is a pure cementum disorder. Vitamin D resistant rickets is a systemic disease with dental manifestations that can be the first overt signs of this syndrome. The clinical evidence of this problem is the spontaneous appearance of abscesses and fistulae in teeth that have no other obvious lesions. The problem affects both primary and permanent teeth. This condition rarely affects enamel but appears to have its effects largely confined to dentin. 2o Abnormalities in Tooth Shape When enamel and dentin are formed correctly but the final shape of the tooth is abnormal, the abnormality appears to be in morphodifferentiation. Here findings such as conical teeth (see Fig. 4), mulberry molars, taurodontism, and other such entities are seen. There are genetic conditions that have as a frequent occurrence some of these findings. Patients with Down syndrome and ectodermal dysplasia often have conically shaped teeth, for example. These abnormalities can also be seen in conjunction with abnormalities of the enamel or dentin and therefore cannot always be localized to one particular stage in development. Abnormalities in Apposition Abnormalities in the apposition stage of tooth development are seen most frequently on an isolated basis. Small but normally shaped teeth are most often seen in the third molar or lateral incisor regions. True microdontia (generalized small teeth) is rarely seen, although it is reported to occur in individuals with Turner syndrome and hypopitu-

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Figure 7. Various types of amelogenesis imperfecta. A, Autosomal dominant Figure 7. Various types of amelogenesis imperfecta. A, Autosomal dominant hypo-hypoplastic defect. B, Autosomal dominant hypocalcification defect. C, Autosomal recessive plastic defect. B, Autosomal dominant hypocalcification defect. C, Autosomal recessive hypomaturation defect. hypomaturation defect.

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Figure 8. 8. Radiograph Radiograph of of teeth in patient patient with dentinogenesis dentinogenesis imperfecta. Note Note bulbous shaped crowns, thin, pointed roots, Figure and partially partially calcified calcified pulp pulp canals. canals. and

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itary gland function. Likewise, true macrodontia (generalized oversized teeth) is very rare and is only seen in hyperpituitary gland function or hemihypertrophy. More common is relative microdontia or macrodontia where the tooth size is normal but the size of the mandible or maxilla is larger or smaller than would be expected from the size of the teeth.20 Localized pitting or hypoplasia of enamel is seen fairly often. The exact cause is not understood but the result is localized regions, either isolated or generalized, where deficient amounts of enamel were laid down. Systemic conditions such as vitamin D dependent rickets result in severe enamel hypoplasia of the occlusal and incisal ename1. 21 Another condition in which an increased frequency of enamel hypoplasia has been reported is tuberous sclerosis. Abnormalities in Calcification Problems that arise in the calcification stage of tooth development affect the hardness of the mineralized tissue. When a problem with calcification affects the enamel, for example, it would be less resistant to acid attack by microorganisms. If the dentin is the tissue affected, the strength of the major supporting structure of the tooth is damaged. Some forms of amelogenesis imperfecta appear to be caused by a problem in calcification of the tissue (see Fig. 7). Whether this abnormality is because of defective calcification of an underlying normal matrix or defective calcification resulting from an abnormal matrix is not known. Abnormalities in Eruption and Shedding of Teeth There is a broad range of variation in the normal eruption times of the deciduous and permanent teeth (see Tables 3 and 4). Because of this inherent biologic variation, it is difficult to determine when the eruption dates for a given person are outside normal limits. Nevertheless, certain eruption times are grossly beyond the extremes of normal and may be considered pathologic, although the significance of this is frequently not apparent. 20 Various factors have been implicated in the control of eruption: genetic, environmental, and systemic. Socioeconomic levels, which affect nutrition and personal hygiene, 8 have also been linked to retarded eruption of anterior teeth and accelerated emergence of posterior teeth. Low birth weight has been associated with delayed eruption of permanent teeth. Conversely, early eruption has been associated with increased birth weight. 20 Abnormalities in eruption times can also be seen in conjunction with several genetic conditions. Some of these are listed in Table 7. If deciduous teeth emerge before the first 3 months oflife, they are classified as premature. Those that are present at birth are called natal teeth (Fig. 9). Those that erupt during the neonatal period (first month of life) are termed neonatal teeth. Of the total, 90% are premature primary teeth (85% are mandibular incisors) and 10% are supernumerary calcified structures. Natal teeth appear more frequently than neo-

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Table 7. Syndromes and Systemic Disorders Associated with Anomalies of Eruption NEONATAL TEETH

Ellis-van Creveld syndrome Hallermann-Streiff syndrome Pachyonychia congenita syndrome DELAYED ERUPTION

Albright hereditary osteodystrophy Cleidocranial dysplasia Down syndrome Hypothyroidism Hypopituitarism Gardner syndrome Goltz syndrome Incontinentia pigmenti syndrome

PREMATURE ERUPTION

Precocious puberty Hyperthyroidism Hemifacial hypertrophy Sturge-Weber syndrome PREMATURE LOSS

Hajdu-Cheney syndrome (aero-osteolysis syndrome) Hypophosphatasia syndrome Papillon-Lefevre syndrome

natal teeth (3: 1). Autosomal dominant occurrences have been reported. 20 Another condition that appears to be a failure in eruption is seen in oro facial digital syndrome (OFD). Congenitally absent teeth are seen frequently in this condition but are not caused by an early induction problem, because the teeth are usually present in the jaw. The problem rather appears to be attributable to a failure in eruption that disrupts the normal development of the tooth and arrests tooth development.

Figure 9. Neonatal tooth in a newborn.

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Abnormalities in Premature Loss of Teeth Premature loss of teeth is most commonly caused by dental caries or periodontal disease and their complications. Premature development of the succedaneous permanent teeth may also give rise to early shedding. Premature loss of primary teeth may be seen in hypophosphatasia and Papillon-Lefevre syndrome. 2o In hypophosphatasia, the teeth are lost without the resorption of the root and without evidence of local disease. In Papillon-Lefevre syndrome, the teeth are lost because of periodontal disease, which is unusually advanced at a very young age and is accompanied by thick keratotic lesions of the elbows and knees. Premature loss of permanent teeth can also be seen in various chronic metabolic diseases (Table 7).21 CRANIOFACIAL CONSIDERATIONS IN THE DIAGNOSIS OF SYNDROMES Table 8 lists the most common syndromes associated with abnormal structures in the craniofacial region. As previously stated this list is not a complete comeendium; several sources exist that perform this task very well. 4, 11, 13, 4,22 The list is intended to alert the reader to the nature of craniofacial anomalies in this region and the major abnormalities with which they are associated. Clearly it is of greatest value in the young child, because many of the listed disorders are more obvious as serious functional problems develop later in childhood. Head Head circumference is a reliable prognostic indicator for future brain or intellectual development. Macrocephaly is a diagnostic feature of cerebral gigantism (Soto syndrome), which is accompanied, in this case, with overall increase in size. Large size is also characteristic of the Beckwith-Wiedemann syndrome (macroglossia, gigantism, omphalocele), but the head here is not disproportionately large, whereas the tongue is. Several retardation syndromes are associated with microcephaly, which can also be an isolated finding. Cranial ridging is a particularly important finding early in life and is a cardinal feature of craniosynostosis syndromes and can result in plagiocephaly. Early recognition and treatment of craniosynostosis can reduce the degree of cranial and facial asymmetry (Fig. 10), particularly if instituted before 3 months of age. Craniosynostosis can be an isolated finding and involve a single suture or multiple sutures. The commonest single suture involved is the coronal suture. This is usually sporadic and has been correlated with prenatal crowding. Multiple suture involvement can be familial or can be associated with craniosynostotic syndromes. Craniosynostosis of the cranial base sutures, especially those associated with the sphenoid bone, are commonly seen in Apert and Crouzon syndromes. A three-dimensional CT scan is essential for an accurate diagnosis of these conditions. A prominent

Table 8. Craniofacial Considerations in Syndrome Diagnosis STRUCTURE

Head

FEATURE

Macrocephaly

Microcephaly Cranial ridging Prominent forehead Ears

Unilateral tags, pits Bilateral abnormalities

Eyes

Hypertelorism Hypotelorism Missing eyelashes Epibulbar dermoids Small palpebral fissures Confluent eyebrows (synophrys) Downslanting: bilateral Downslanting: unilateral

.... .... o ~

Upslanting

SYNDROME

Hydrocephaly Arrhinencephaly Soto's gigantism Gorlin Mental retardation syndromes Chromosomal Craniosynostosis Achondrodysplasia Apert Cleidocraniodysplasia DeLange Hemifacial dysplasia Goldenhars Kidney aplasia Treacher Collins Nager acrofacial dysostosis Wildervanck-Smith First arch defects Lateral facial clefting Midfacial clefting Holoprosencephaly Treacher Collins Goldenhars Prader-Willi DeLange Treacher Collins Pfeiffer Hemifacial syndromes Craniosynostosis Femoral hypoplasia

CAUSE

Sporadic Sporadic A.D. Various Sporadic or A.D. A.D. A.D. A.D. Various Sporadic Sporadic Sporadic A.D. A.R. Sporadic Various Various Sporadic Various A.D. Sporadic Chromosomal Sporadic A.D. A.D. Various Various

(Table continued on next page)

i-' i-' i-'

o

Table 8. Craniofacial Considerations in Syndrome Diagnosis (Continued) FEATURE

STRUCTURE

Nose

Flattening: unilateral Flattening: central Bifid Small, anteverted Large, bulbous

Maxilla-Mandible

Flattened malar region (maxillary hypoplasia)

Micrognathia

Asymmetric Prognathia

SYNDROME

Cleft lip Holoprosencephaly Maxillonasal dysplasia Chondrodysplasia punctata Warfarin dysplasia DeLange Robinow Hallermann-Streiff Ruvacalva Rubinstein Taybi Pfeiffer Treacher Collins Nager acrofacial Wildervanck-Smith Frontal nasal dysplasia Otopalatodigital Crouzon Apert Hypoglossia hypodactylia Sticklers Hallermann-Streiff Robin sequence Hemifacial microsomia Klippel-Trenaunay-Weber Binders frontonasal Antley Bixler Apert Beckwith-Wiedemann Crouzon

CAUSE

Multifactorial Various Sporadic Sporadic Prenatal warfarin Various A.D. A.D. Sporadic Sporadic A.D. A.D. A.R. Sporadic Sporadic X-linked A.D. A.D. Sporadic A.D. A.D. See above Sporadic Sporadic Sporadic A.D. A.D.

...... ......

Oral opening

Microsomia Macrostomia

Facies

Long, narrow Triangular Wide, short

Oral cavity

Macroglossia Microglossia (aglossia) Multilobulated Bifid Hypermobile Cleft lip and palate

Tongue Lips and palate

Lip pits Cleft palate

Soft tissue of the mouth

Frenula Gingivae

Abbreviations: AD

=

autosomal dominant; AR

=

Otopalatal digital Hallermann-Streiff Facioauriculovertebral M ucopolysaccharidosis Beckwith-Wiedemann Marfan Prader-Willi Fragile X Apert Soto Beckwith-Wiedemann DeLange Beckwith-Wiedemann Hypoglossia-hypodactylic Moebius complex OFDI OFD II Ehlers-Danlos Isolated Syndromic EEC OFD I and II Multiple systems Van der Woude Apert Crouzon Stickler (Robin) OFDI Treacher Collins Fetal hydantoin, methadone Alcohol OFD I and II Ellis-von Creveld Ehlers-Danlos VIII Pap ilion-LeFevre

autosomal recessive.

X-linked A.D. Sporadic Various Sporadic A.D. See above Chromosomal A.D. Sporadic Sporadic Sporadic Sporadic Sporadic Sporadic Dominant (X-linked or autosomal) A.R. Various Multifactorial A.D. See above Chromosomal A.D. A.D. A.D. A.D. See above A.D. Teratogenic See above A.R. A.R.

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Figure 10. Face of a baby with facial asymmetry secondary to craniosynostosis.

forehead or tower skull (taurocephaly) is related to noncorrection of craniosynostosis of the lateral sutures (coronal or lambdoid) and is seen in Apert syndrome. A bulging forehead is often seen in DeLange syndrome and achondroplasia. This could be caused by failure of growth of the cartilage in the cranial base. Ears The external and middle ear are formed from derivatives of the first and second branchial arches. Reduction in ear size and abnormalities in position are associated with abnormal development early in embryogenesis. The ears can be small because of absence of certain components (i.e., helix, antihelix, lobe, tragus), which gives a cupshaped, lobulated, crumpled, or flattened ear (Fig. 11). The ear is low set or rotated because of failure of embryonic migration between the first and second arch. This can be associated with tags that are located on a line from the ear to the corner of the mouth. Bilateral rudimentary or crumpled ears that are low set and rotated are common in the Treacher Collins syndrome (mandibulofacial dysostosis). This syndrome also has a small lower jaw (micrognathia), midfacial flattening, downslanting eyes, and absence of the medial third of the lower lid eyelashes. Nager's acrofacial dysostosis mimics Treacher Collins syndrome. Unilateral ear abnormalities with associated tags are seen in hemifacial microsomia (dysplasia) and its related disorder, Goldenhars syndrome (facioauriculovertebral anomalad). Hemifacial dysplasia is

THE CRANIOFACIAL COMPLEX AND CONGENITAL MALFORMATIONS

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Figure 11. Abnormal external ear in a young infant. Note ear tags also.

an isolated finding involving the external ear and facial asymmetry caused by failure of development of the condylar head on that side. When this abnormality is associated with vertebral and rib abnormalities and epibulbar dermoids, the more likely diagnosis is Goldenhars syndrome. Variants involving the facial nerve exist and these can produce unilateral facial palsy with associated abnormalities in closure of the eyelids. Floppy ears are often caused by failure in cartilage development and may be attributable to collagen defects. Microtia (small, malformed, crumpled ears) can be associated with kidney defects, and the latter should be ruled out as part of the report of these patients. 7 Eyes The position of the eyes is also determined early in embryogenesis as they move from a lateral position to their normal midface position as this area develops and grows. Failure of midface development can lead to hypotelorism, such as that seen in holoprosencephaly (Fig. 12). Hypertelorism (increased interpupillary distance) can also be caused by failure in development of the midface due to clefting syndromes or growth of the nasal root with associated flattening and telecanthus (increased in inner canthal distance) (Fig. 13). Downslanting eyes are hypothesized to be caused by failure of development of the root of the zygoma (e.g., Treacher Collins syndrome). Abnormalities of the eyelashes and eyebrows are seen in several syndromes but can be related to generalized defects in ectoderm (ectodermal dysplasias). Reduction in the size of the globe of the eye produces reduction in the size of the orbit, which can lead to midfacial hypotrophy, small palpebral fissures, and ptosis, which are part of many syndromes. Visual abnormalities caused by genetically inherited structural defects in the lens or retina are associated with primary collagen and elastin defects.

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Figure Figure 12. 12. Face Faceof ofaachild child with with holoprosencephaly. holoprosencephaly. Note Note midline midline cleft of the lip and hypotelorism. hypotelorism.

Figure 13. 13. Face Face of of aa child child with with repaired repaired cleft cleft lip lip and and hypertelorism hypertelorism with with teleteleFigure canthus. canthus. Note coloboma coloboma of ofthe the left left eye. eye.

THE CRANIOFACIAL COMPLEX AND CONGENITAL MALFORMATIONS

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Nose The nose is clearly affected by any abnormal development and growth of the midface. Nasal cartilage (septal and external) contributes to anterior growth of the midface, especially the maxilla; damage to it leads to a concave facial profile. Thus, nasal structural abnormalities are seen in conditions already discussed where the malar region, the root ofthe nose, or the maxillary area are significantly hypoplastic (e.g., holoprosencephaly, cleft lip and palate, and maxillonasal dysplasia). A bifid nose (Fig. 14) can be related to abnormalities in cartilage development (chondrodysplasia punctata, which are due to peroxismal enzyme defects) in which this is an isolated finding or part of a generalized abnormality. A special case is the bifid nose seen in prenatal warfarin exposure. A small antiverted nose or a large bulbous nose are part of many syndromes, some of which are listed in Table 8.

Maxilla-Mandible Mandibular defects can be classified as micrognathia, asymmetrical bone growth, or as overgrowth of the mandible (prognathism). Micrognathia is again a common feature of many syndromes, some of which are listed in Table 8. Of particular note is the Robin sequence, in which abnormal cranial flexure early in embryogenesis may lead to micrognathia and a U-shaped or V-shaped cleft of the palate (Fig. 15). Respiratory, cardiac, and feeding problems are common in newborns with this condition. Careful management of the respiratory problems and avoidance of glossoptosis (closure of the airway by the tongue) is essential in these patients if survival is not to be jeopardized. Many

Figure 14. Child with a bifid nose.

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Figure 15. Lateral view of child with the Robin sequence defect. Note small lower jaw (micrognathia). Child also had a U-shaped cleft of the palate and significant respiratory difficulties when placed on its back.

patients with Robin sequence have associated syndromic disorders, the most common being Stickler syndrome, some of which have been found to be caused by a type II collagen disorder affecting primarily those tissues rich in type II collagen. This disorder should be ruled out in all babies with the Robin sequence. Robin sequence is also seen in fetal alcohol, fetal methadone, and fetal Dilantin syndromes. Meckel's cartilage is the embryonic inducer of the mandible and is retained postnatally in the growing condylar head and in the malleus of the middle ear. Thus, micrognathia is commonly associated with abnormalities of the external or middle ear, including middle ear deafness, absence of the external auditory meatus, and external ear abnormalities. Mandible size is commonly related to the size of the soft tissues attached to it. A small tongue often is associated with micrognathia, whereas macroglossia is associated with prognathism (e.g., in the Beckwith-Wiedemann syndrome). Prognathism can be a relative term used to compare the lower jaw to the upper jaw. Midfacial or maxillary hypoplasia can appear clinically as prognathism. This is seen, for example, in older individuals with Down syndrome. True prognathism is commonly inherited but can also develop in adults because of excessive growth hormone (acromegaly). Hemifacial mandibular abnormalities associated with a unilateral condylar defect have been discussed

THE CRANIOFACIAL COMPLEX AND CONGENITAL MALFORMATIONS

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earlier but should be distinguished from hemihypertrophy. This is seen, for example, in Klippel-Trenaunay-Weber syndrome, which not only has facial asymmetry, but also generalized somatic hemihypertrophy associated with multiple hemangioma and growth hormone deficiency. Interestingly, this syndrome produces right to left differences in dental development (Fig. 16). Maxillary hypoplasia, as already discussed, is associated very commonly with malformation or abnormal development of the midfacial region in general (maxillonasal syndrome). Binders syndrome can be caused by failure of maxillary development with production of relative prognathism. Correction of this disorder may necessitate surgical maxillary advancement and mandibular retrusion in the teenaged years, once growth has ceased, but in the interim a progressive "dished in" or concave face results. This is a benign condition, however, and is to be distinguished from frontonasal dysplasia, which has significant hypertelorism and a possible median facial cleft. Treatment of the latter may involve more significant facial surgery, particularly if alternating strabismus is noted. Many of the syndromes listed in Table 8 under this heading have been discussed elsewhere. Oral Opening The oral opening can be described as very small (microstomia) or very large (macrostomia). Even in very small, young infants, the mouth

Figure 16. Lower jaw of patient with Klippel-Trenaunay-Weber syndrome. Note unilateral delayed dental development (arrow). Patient has multiple hemangioma, body asymmetries, and short stature.

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can be opened to a vertical distance of 2.5 cm to 3 cm. The intercommissural distance varies from a mean of 27 mm in infancy to 50 mm in adulthood, with girls generally having smaller measurements than boys at any given age. 3 Although these measurements are often difficult to perform on conscious children, they do give some point of reference for the assessment of these pathologic stigmata. Otopalatodigital syndrome is a condition manifested by deafness, cleft palate, and characteristic hands and feet having short, broad phalanges and curved toes and fingers. The oral opening is generally small and associated with midfacial hypoplasia but characteristic lateral supraorbital bossing. It is an X-linked dominant condition with semidominant expression in women. The Robinow syndrome (fetal face syndrome)14 is also associated with midfacial flattening and a small, bow-shaped oral opening. Microcephaly is common, with a large anterior fontanelle that closes late. Shortening of the forearms and abnormal genitalia are characteristic. Hallermann-Streiff syndrome has microstomia as a common feature, in conjunction with micrognathia, brachycephaly, frontal bossing, flattened midface, and a small, thin nose. Macrostomia is commonly the result of failure of fusion of the embryonic maxillary and mandibular processes in early prenatal development. In the mucopolysaccharidoses, however, the large oral opening may be secondary to the enlargement of the soft tissues, especially the tongue, and is not particularly diagnostic of these conditions. As an embryologic defect, macrostomia can be an isolated event or part of the teratogenic effects involving all of the first arch derivatives. Relative macrostomia is found occasionally in the facioauriculovertebral anomalad.

Facies Dolichocephaly (long, narrow face) is often related to increased downward and forward development of the face as a whole. This produces a so-called "lantern jaw" appearance associated with a steep mandibular plane (lower border of the mandible) (see Fig. 1). The mandibular plane in the upright rest position is normally at about a 5° to 10° angle to the floor. This long face appearance is often seen in collagen or elastin defects, such as the Marfan syndrome, and in these cases is obviously associated with other skeletal abnormalities, such as visual and cardiac defects. Prader-Willi syndrome, by measurement, has dolichocephalic facies despite the fact that clinically the obesity suggests differently. Brachycephaly (short, broad face) is characteristic of the normal face of people of Asian origin but is also seen in a more exaggerated form in some syndromes, including those listed in Table 8. The overall shape of the face can be changed by differential growth of its individual components. Macrocephaly can produce a wide upper face and this, associated with a relatively normal lower face, produces an overall triangular shaped face (e.g., Soto syndrome). Similar effects can be the result of a very small, posteriorly positioned chin (retrognathia).

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Oral Cavity The oral cavity is discussed under three headings: the tongue, lips and palate, and the soft tissues of the mouth. Clearly, the teeth have been discussed in detail earlier. Tongue. The tongue can be altered either in size, shape, or mobility. Macroglossia is a relative term referring to an actual increase in the volume of the tongue. In Beckwith-Wiedemann syndrome (exophthalmos-macroglossia-gigantism [Fig. 17] the tongue is very large, often protrudes from the mouth, and can be extended a considerable distance without narrowing. Persistence of this tongue size can cause significant feeding problems and, usually later, divergence and protrusion of the lower anterior teeth. Increase in tongue size can also be associated with a short neck and anterior placement of the hyoid bone (as in Down syndrome). In Down syndrome, surgical correction is not always indicated, but this is often necessary in Beckwith-Wiedemann syndrome. Microglossia (hypoglossia) or aglossia (Fig. 18) is seen in aglossia-adactylia syndrome, usually in association with hypoplastic alveolar ridges, micrognathia, and limb reduction deformities. Babies with this syndrome often have some feeding problems in the newborn period. A small tongue is also a feature of congenital facial diplegia (Moebius complex). Alteration in tongue shape produces such abnor-

Figure 17. Facial photograph of a patient with Beckwith Wiedemann syndrome. Macroglossia that severely occluded the airway necessitated tracheostomy.

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hypoglossia-hypodactylia syndrome. syndrome. Figure 18. Microglossia in hypoglossia-hypodactylia

malities as lobulated or bifid bifid tongue tongue (Fig. (Fig. 19). 19). These These abnormalities abnormalities of of of misplacement misplacement of of the the frenulum frenulum or or to to the tongue can be the result of is seen seen in in OFD OFD syndrome syndrome (OFD (OFD II and and II). II). additional frenula as is type I is is seen seen only only in in girls girls in in whom whom the the tongue tongueisis Oral facial digital type multilobulated and and is is associated associated with with abnormal abnormal frenula frenula extendextendoften multilobulated cheeks and and lips lips over over the the alveolar alveolar ridges ridges (Fig. (Fig. 20). 20). It Itconsists consists ing from cheeks additionally of characteristic characteristic facies, facies, asymmetrical asymmetrical limb limb reduction reduction dedeadditionally with clinodactyly, clinodactyly, and and cleft cleftpalate. palate. These Thesechildren childrenneed needear~y ear~y formities with

Figure19. 19.Bifid Bifidtongue tongueassociated associatedwith withoral-facial-digital oral-facial-digitalsyndrome syndrometype type1.1. Figure

THE CRANIOFACIAL COMPLEX AND CONGENITAL MALFORMATIONS

1121

Figure 20. Oral cavity of child with oral-facial-digital syndrome type 1. A, Maxillary arch showing cleft alveolus bilaterally associated with a left unilateral cleft of the lip. B, Mandibular arch showing similar clefts in the alveolus with extra frenulae.

careful observation for more generalized defects (such as renal defects), and many die in infancy. OFD II (Mohr syndrome) is generally less severe and the tongue is more frequently bifid; hyperplastic frenula do occur and conductive deafness is frequently associated.

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Change in the mobility of the tongue can be the result of a short or thickened lingual frenum and can be part of OFD I and II or the Ellis-van Creveld syndrome. Hypermobility of the tongue is common in the various types of Ehlers-Dan los syndrome, in which hyperextensibility of the tongue is common. Benign forms of this syndrome are often not recognized until the teenaged years. The ability to extend the tongue to the tip of the nose is a frequent sign. Lips and Palate. The lips and palate can obviously be affected by clefting. Cleft lip results from abnormal approximation or fusion of the maxillary and median frontonasal processes early in embryonic development (sixth to eighth week). Cleft lip can be found alone or in conjunction with cleft palate but in both cases almost always involves cleft of the alveolus with associated dental abnormalities. Cleft lip and palate can be isolated (i.e., no other associated anomalies) or in conjunction with known syndromes, provisionally unique syndromes, or associated anomalies. Recent analysis of cases seen at the University of Connecticut Health Center16 suggest that very few clefts (Table 9) fit into the isolated category. This also has been reported by others.6 Clefts in the isolated category are generally considered multifactorial in origin (i.e., the result of multiple genes interacting with each other and unknown environmental insults), but this conclusion is still undergoing considerable debate. A few of the syndromes associated with cleft lip are shown in Table 8; Cohen5 and Gorlin et aP3 have listed several hundred other syndromes. These syndromes affect multiple body systems and have a wide range of morbidity and mortality. The more diverse the organ systems involved, the more likely the disorder involves a chromosomal abnormality. A separate category of clefts is associated with pits of the lower lip. Van der Woude's lip pit syndrome is a single gene defect in which family members have lip pits, cleft lip or palate, or both. 3 Recognition of this and other single gene clefting disorders is essential to accurate genetic counseling. Cohen5 , 6 estimates that more than 50% of all syndromic clefts are single gene defects.

Table 9. Diagnostic Factors in Patients with Cleft Lip and Palate or Cleft Palate FACTOR

NUMBER

Maternal drug exposure Positive family history Identifiable syndrome Provisionally unique syndrome Associated anomalies (nonsyndromic) Robin anomaly Isolated cleft

15 37 27 29 53 17 28

PATIENTS

(%)*

8.6 21.1 15.4

16.6 30.3 9.7 16.0

* Percentage of total patients with clefts attending University of Connecticut Health Center Craniofacial Clinic from 1982 to 1987 (n = 175). Note: Some patients were included in more than one category.

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Cleft palate alone (i.e., without cleft lip) is often considered to be a different defect than cleft lip,lO although this is not universally accepted. 17 The Robin sequence has been discussed earlier in conjunction with micrognathia, but isolated cleft palate is also seen as part of other syndromes, some of which are listed in Table 8. It is important to remember that many more exist. Of particular note are submucous cleft palate (a bony defect of the hard palate) or bifid uvula, which are not readily visible clinically and may remain undetected for years. As a microform of cleft palate, their presence may make a substantial difference to recurrence risk. Failure to ascertain these minor abnormalities may make some of the cleft lip and cleft palate data in the literature inaccurate. Soft Tissues. Soft tissues of the oral cavity listed in Table 8 include abnormalities of the frenula and gingiva. The frenula associated with OFD I and II have been discussed earlier. Characteristic multiple frenula extending over the alveolar ridge and giving it a lobular appearance in the newborn is a feature of Ellis-van Creveld syndrome (chondroectodermal dysplasia). These children also have neonatal teeth (25%), severe prenatal growth delay with mesomelic dwarfism, ectodermal dysplasia (especially of the nails), and congenital heart defects (50%). Gingival abnormalities are of two broad general categories: those with periodontal disease and those with gingival hyperplasia or overgrowth. 20 Periodontal diseases are very common in the adult population, and 90% or more have gingival inflammatory disease with gradations from simple gingivitis to advanced periodontal disease with alveolar bone loss and tooth mobility. The bacterial origin of these diseases is undoubted. Advanced periodontal disease in children is

Figure 21. Gingival fibromatosis. Note swelling and overgrowth of the soft tissue around the teeth.

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uncommon but is seen in acute juvenile periodontitis, a specific disorder leading to mobility and potential loss of molars and incisors. Some forms of this disorder are familial and a gene has been localized to the long arm of chromosome 4. Ehlers-Danlos syndromes, in general, are associated with periodontal disease but the type VIII syndrome appears to be a condition with minimal joint and skin involvement but significant periodontal disease. 23 Papillon-Lefevresyndrome is associated with significant bone loss around the teeth that ultimately leads to their loss. Gingival enlargement is commonly associated with taking phenytoin, with isolated hereditary gingival fibromatosis (Fig. 21), and with several blood dyscrasias. It is also seen in Cowden syndrome,20 a condition characterized by multiple neoplastic lesions in the breast, thyroid, ovaries, and so on and with papillomatous lesions of the gingiva, palate, and tongue. This is an autosomal dominant syndrome. SUMMARY This article was meant to be a very cursory survey of the multiple defects that abnormal development can produce in all areas of the craniofacial complex. Careful examination for these abnormalities should lead the clinician to earlier referral of patients for additional examination by a genetics team. This often enables more focused care for the individual and better counseling concerning future pregnancies. Aase points out that "funny looking face" or "syndromic facies" is no longer helpful. l Accurate assessment of the face with measurement leads to better diagnosis and ultimately better patient care. All children with facial defects deserve early intervention by a multidisciplined craniofacial team including geneticists, surgeons, dentists, speech pathologists, and other specialists. Part of the process of early referral to this team involves early detection and recognition in the neonatal period. It is hoped that this article stimulates the pediatrician to be aware of these abnormalities, recognize their importance, and seek additional help for patients, no matter what their age. REFERENCES 1. Aase JM: Diagnostic Dysmorphology. New York, Plenum Medical Book Co, 1990 2. Buyse MI: Birth Defects Encyclopedia. Dover, Center for Birth Defects Information Services, Inc., 1990 3. Cervanka J, Gorlin RJ, Anderson VE: The syndrome of pits of the lower lip and cleft lip and/or palate: Genetic considerations. Am J Hum Genet 19:416, 1967 4. Cohen MM Jr: Dysmorphic syndromes with craniofacial manifestations. In Stewart RE, Prescott GH (eds): Oral Facial Genetics. St. Louis, C.V. Mosby Co, 1978 5. Cohen MM Jr: Syndromes with cleft lip and cleft palate. Cleft Palate J 15:3006, 1978 6. Cohen MM Jr, Bankier A: Syndrome delineation involving orofacial clefting. Cleft Palate-Craniofacial Journal 28:119, 1991 7. Cremers CWRJ, Fikkers-von Noord M: The earpit-deafness syndrome. Clinical and genetic aspects. Int J Pediatr OtorhinolaryngoI2:309, 1986

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8. Dixon GH, Stewart RE: Genetic aspects of anomalous tooth development. In Stewart RE, Prescott GH (eds): Oral Facial Genetics. St. Louis, C.V. Mosby Co, 1976 9. Feingold M, Bossert WH: Normal values for selected physical parameters: An aid to syndrome delineation. Birth Defects 10:1, 1974 10. Fogh-Anderson P: Inheritance of harelip cleft palate. Copenhagen, Munksgaard, 1942 11. Goodman RM, Gorlin RJ: Atlas of the Face in Genetic Disorders. St. Louis, C.V. Mosby Co, 1977 12. Gorlin RJ: Diagnosis of craniofacial anomalies: Subjective evaluation-gestalt. In Salinas CF, Jorgenson RJ (eds): Dentistry in the Interdisciplinary Treatment of Genetic Diseases. Birth Defects: Original Article Series, Vol XVII, 1980, pp 35-46 13. Gorlin RJ, Cohen MM Jr, Levin LS: Syndromes of the Head and Neck, ed 3. Oxford Monographs on Medical Genetics #19, New York, Oxford University Press, 1990 14. Jones KL: Smith's Recognizable Patterns of Human Malformation. Philadelphia, W.B. Saunders Company, 1988 15. Schaeferr WG, Hine MK, Levy BM: A Textbook of Oral Pathology, ed 4. Philadelphia, W.B. Saunders Company, 1983, pp 2-85 16. Schardt DM, Poole AE: Multiple etiology of cleft lip and palate. In Programs and Abstracts of the 18th Annual Session of the American Association of Dental Research. San Francisco, 1989, p 248 17. Shapiro BL: The genetics of cleft lip and palate. In Stewart RE, Prescott GH (eds): Oral Facial Genetics. St. Louis, C.V. Mosby Co, 1976 18. Smith DW: Classification, nomenclature and meaning of morphologic defects. J Pediatr 87:162, 1975 19. Smith DW: Recognizable Patterns of Human Malformations, ed 2. Philadelphia, W.B. Saunders Company, 1976 20. Stewart RE, Poole AE: The orofacial structures and their association with congenital anomalies. Pediatr Clin North Am 29:547,1982 21. Stewart RE, Barber T, Troutman K, et al: Pediatric Dentistry: Scientific Foundations for Clinical Practice. St. Louis, C.V. Mosby Co, 1981, pp 87-134 22. Stewart RE, Prescott GH: Oral Facial Genetics. St. Louis, C.V. Mosby Co, 1976 23. Stewart RE, Hollister DW, Rimoin DL: A new variant of Ehlers-Danlos syndrome. Birth Defects 13:85, 1977 24. Witkop CJ, Sauk JJ: Heritable defects of enamel. In Stewart RE, Prescott GH (eds): Oral Facial Genetics. St. Louis, C.V. Mosby Co, 1976

Address reprint requests to Andrew E. Poole, BDS, MS, PhD Department of Pediatric Dentistry University of Connecticut Health Center 263 Farmington Ave. Farmington, CT 06030